ACC: Rimonabant Therapy Fails to Demonstrate Atherosclerosis Benefit

By Peggy Peck
CHICAGO, April 2 -- Reducing abdominal obesity with the investigational diet drug rimonabant had a beneficial effect on metabolic profile, but did not demonstrate a significant reduction in percent atheroma volume on intravascular ultrasound, researchers reported here. But there was a significant improvement in a prespecified secondary endpont, total atheroma volume, which led Steven Nissen, M.D., of the Cleveland Clinic, to conclude that a weight reduction strategy that targets abdominal obesity is promising. Dr. Nissen, who presented the results of the STRADIVARIUS (Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant) trial at the American College of Cardiology meeting, said that it is also possible that larger trials of rimonabant or a similar agent might provide evidence of a direct effect on atherosclerosis.
After 18 months of treatment the percent atheroma volume, a measure of plaque in the artery wall, increased in 0.25% in the rimonabant group versus an increase of 0.51% in the placebo arm (P=0.22).
But the total atheroma volume decreased by 2.2 mm2 in the rimonabant arm versus an increase of 0.88 mm2 in the placebo arm (P=0.03).
Moreover, rimonabant therapy was associated with an increase of 5.8 mg/do in HDL, a decrease of 24.8 mg in triglycerides, and a decrease of 1.3 mg/do in C-reactive protein, all of which were significant compared with controls (P<0.001).
Glycated hemoglobin increased in both arms, but the rate of increase was significantly slowed in the rimonabant group (0.11% versus 0.40% P<0.001).
That finding, while not raising to the level of solid evidence, was hypothesis-generating and enough, Dr. Nissen said, to suggest that there was a possibility that CRESCENDO, a large, ongoing outcomes trial of the drug, might provide evidence of real cardiovascular benefit.
The finding was also one more disappointment for what was once widely regarded as a promising drug.
Rimonabant has repeatedly demonstrated its efficacy for weight loss and has also demonstrated efficacy in smoking cessation trials. That evidence paved the way for quick approval in Europe, but the FDA said it won't approve the drug without more safety data.
STRADIVARIUS randomized 839 patients at 112 centers in North America, Europe, and Australia to 20 mg rimonabant or placebo, plus dietary counseling. All patients had baseline intravascular ultrasound and 676 had repeat IVUS on completion of the trial.
The mean baseline body mass index of patients was 35 and the mean waist circumference for men, who made up 65% of the study participants, was 46 inches.
Patients in the rimonabant arm shed about 9.5 pounds (4.3 kg) versus 1.1 pounds (0.5 kg) in the controls. They also reduced their waist circumference by 1.77 inches (4.5 cm) versus a decrease of 0.39 inches (1.0 cm), P<0.001 for both.
Although there was not a clear indication of cardiovascular benefit, there was a significant safety signal in the trial -- 43.3% of the rimonabant patients reported anxiety, depression, and other mood disorders versus 28.4% of the placebo patients (P<0.001).
Moreover, one patient in the placebo group attempted suicide and one patient in the rimonabant arm completed suicide.
It was concern about psychiatric side effects that derailed rimonabant's bid for FDA approval.
As noted in a editorial that accompanied the JAMA publication, an FDA analysis of rimonabant clinical trials found that the 20 mg dose "was associated with a 2-fold higher suicide risk," and an FDA advisory committee unanimously recommended against rimonabant approval.
Asked about the likelihood that rimonabant would ever be available in the United States, Dr. Nissen declined to speculate, but he said that similar compounds are in development, which increased the likelihood that a cannabinoid receptor blocker will eventually win FDA approval.
In the JAMA editorial, John S. Rumsfeld, M.D., Ph.D., of the University of Colorado at Denver, and Brahmajee K. Nallamothu, M.D., M.P.H., of the University of Michigan in Ann Arbor, concluded that until the results of the CRESENDO study are available, "the potential benefits of rimonabant therapy are offset by very real risks of depression and anxiety."
Attacking abdominal obesity as a way to lower lipids is not a novel concept. In November 2005, the RIO-LIPIDS (Rimonabant in Obesity Lipids) investigators wrote that 12 months of treatment with rimonabant, plus a diet that cut daily energy intake by 600 calories was associated with significant improvement in lipids (N Engl J Med 2005; 353: 2121-2134).
And a year earlier, results from the 30,000-patient INTER-HEART study, reported at the European Society of Cardiology and simultaneously published in The Lancet, showed that one of the most potent predictors of cardiovascular risk was waist circumference irrespective of waist or gender (The Lancet, 2004 364: 953-62)
The study was funded by sanofi-aventis.
Dr. Nissen reported receiving research support from AstraZeneca, Atherogenics, Eli Lilly, Novartis, Pfizer, Takeda, Daiichi-Sankyo, and sanofi-aventis and consulting for a number of pharmaceutical companies without financial compensation (all honoraria, consulting fees, or any other payments from any for-profit entity are paid directly to charity, so that neither income nor any tax deduction is received).
Drs. Rumsfeld and Nallamothu reported no financial conflicts.
Additional source: Journal of the American Medical AssociationSource reference: Nissen, SE et al "Effect of Rimonabant on Progression of Atherosclerosis in Patients with Abdominal Obesity and Coronary Artery Disease The STRADIVARIUS Randomized Controlled Trial" JAMA 2008; 299: 1547-1560. Additional source: Journal of the American Medical AssociationSource reference: Rumsfeld JS, Nallamothu BK "The hope and fear of rimonabant" JAMA 2008; 299: 1601-1602.